THYMOCYTE APOPTOSIS INDUCED BY P53-DEPENDENT AND INDEPENDENT PATHWAYS
THYMOCYTE APOPTOSIS INDUCED BY P53-DEPENDENT AND INDEPENDENT PATHWAYS
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DOI：
10.1038/362849a0
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发表时间：
1993-04-29
期刊：
影响因子：
64.8
通讯作者：
WYLLIE, AH
中科院分区：
文献类型：
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作者：
CLARKE, AR;PURDIE, CA;WYLLIE, AH
在胚胎发育、T细胞和B细胞成熟以及内分泌诱导的萎缩过程中，细胞的缺失是细胞死亡的特征。细胞凋亡可由多种药物1-5启动，可能是肿瘤抑制基因P53(参考文献6-8)表达的结果。在这里，我们研究了胸腺皮质细胞中P53表达对细胞凋亡的依赖性。从构成杂合子或纯合子的小鼠制备短期胸腺细胞培养，用于基因打靶后引入生殖系的p53基因的缺失。野生型胸腺细胞在电离辐射、糖皮质激素甲基强的松龙或依托泊苷(拓扑异构酶II的抑制剂)处理后，或在佛波酯和钙离子载体依赖于钙的激活后，很容易发生凋亡。相比之下，P53基因缺失的胸腺细胞对辐射或依托泊苷诱导的凋亡具有抵抗力，但对糖皮质激素和钙保持正常的敏感性。在未经处理的培养物中发生的依赖时间的细胞凋亡不受P53状态的影响。P53缺失杂合子细胞对辐射和依托泊苷有部分抵抗力。我们的结果表明，P53在启动细胞凋亡中发挥着显著的剂量依赖效应，但只有当它是由导致DNA链断裂的药物诱导时才起作用。
DEATH by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy1. Apoptosis can be initiated by various agents1-5 and may be a result of expression of the oncosuppressor gene p53 (refs 6-8). Here we study the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca2+-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time-dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Our results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage.